Colchicine (1), a natural product isolated from Colchicum autumnale (Meadow Saffron) has been used for the treatment of rheumatic condition ‘gout’ and also for the treatment of familial Mediterranean fever, pericarditis, and Behcet's disease (Cocco G. et al., Eur. J. Intern. Med. 2010, 21, 503-508; Niel E. et al., Joint Bone Spine 2006, 73, 672-678; Terkeltaub, R. A., Semin. Arthritis Rheum. 2009, 38, 411-419). Colchicine exhibits potent anticancer activity by binding to tubulin, inhibiting its self-assembly and microtubule polymerization and finally arresting cell division at metaphase. Colchicine interacts mainly with three proteins viz. tubulin, cytochrome P4503A4 (CYP3A4), and P-glycoprotein (P-gp). CYP3A4 is the major protein found mainly in liver and intestine which metabolizes colchicine by demethylating the —OMe groups at C-2 and C-3 positions. The development of tumor resistance to colchicine mainly occurs via its P-gp substrate and induction activity, and increase in the expression of βIII tubulin isotype (Niel E. et al., Joint Bone Spine 2006, 73, 672-678; Druley T. E. et al., Biochemistry 2001, 40, 4323-4331; Tateishi T. et al., Biochem. Pharmacol. 1997, 53, 111-116).
The P-gp induction is responsible for the multidrug resistance particularly in the case of cancer cells and makes the currently available chemotherapy ineffective (Ling V., Cancer Chemother. Pharmacol. 1997, 40, S3-S8; Aller S. et al., Science 2009, 323, 1718-1722). Therefore, the search for cytotoxic compounds which are devoid of multidrug resistance is of great importance (Lage H., Cell. Mol. Life Sci. 2008, 65, 3145-3167). Colchicine (1) is a substrate of P-gp efflux pump and it induces its activity by inducing conformational change (Druley T. E. et al., Biochemistry 2001, 40, 4323-4331). To overcome the P-gp mediated resistance of colchicine, Cosentino et al. demonstrated that its N-benzylated derivative (2) showed no loss in cytotoxic activity in the resistant A2780AD ovarian carcinoma cells which are known to overexpress the ABCB1 drug transporter (Cosentino L., J. Med. Chem. 2012, 55, 11062-11066).

Several patents have been published related to colchicine and their compounds for the treatment of inflammatory diseases, antiproliferative, gout, anti-tumor, etc. Thorson et al. have synthesized series of neoglycosides of colchicine with cytotoxic activity (U.S. Pat. No. 8,232,254). Nielsen et al. (US20110184061), Nielsen et al. (WO2011091114) and Bombardelli et al. (WO1996011184) have designed thiocolchicine and colchicine derivatives suitable for use as a muscle relaxant, an anti-inflammatory agent, as an anti-gout agent, as an anti-proliferative agent, or as an anti-cancer agent. Tuszynski et al. (US20120225912), Brown et al. (WO2002056872) and Alberta health services (WO2011022805) have synthesized and patented colchicine derivatives for targeting cancer diseases. Han et al. have patented several colchicine derivatives for immunomodulatory action (US20130011417). Colchicine is also patented for control of retroviruses by The Rockefeller University USA (WO1989012444). Fringuelli et al. have synthesized and patented colchicine derivatives for the antifibrotic treatment of chronic hepatic diseases (WO2008102397). Mutual Pharmaceutical Company, Philadelphia, USA have used colchicine and macrolide antibiotics to inhibit P-glycoprotein in order to enhance the effect of colchicine. To the best of our knowledge, there is no patent where the P-glycoprotein induction liability of colchicine scaffold has been reduced by the structural modification of colchicine (U.S. Pat. No. 7,935,731).
Recent report on the discovery of 3D-structure of P-gp from Caenorhabditis elegans, encouraged us to use 3D-crystal structure of P-gp to design colchicine derivatives for addressing its issue of P-gp induction liability (Jin M. S., Nature 2012, 490, 566-569). The structure-activity relationship (SAR) of colchicine as anti-tubulin agent (Cosentino L., J. Med. Chem. 2012, 55, 11062-11066; Andreu J., Biochemistry 1982, 21, 6465-6476; Das L., Biochemistry 2005, 44, 3249-3258; Cifuentes M., Bioorg. Med. Chem. Lett. 2006, 16, 2761-2764; Zefirova O. N., Bioorg. Med. Chem. 2011, 19, 5529-5538; Nakagawa G. K., Bioorg. Med. Chem. Lett. 2005, 15, 235-238; Boyer F. D., Bioorg. Chem. 2010, 38, 149-158; Chen J., Mini Rev. Med. Chem. 2009, 9, 1174-1190) is available in the literature, however its SAR for P-gp induction activity has not been examined. The limitation of colchicine in the treatment of cancer is due to its P-gp liability. The present invention reports discovery of 10-substituted colchicinoids with better in vitro and in vivo anticancer activity than colchicine, and with reduced P-gp induction liability.